Targeted Corrective Gene Conversion (TCGC): Application in DMD mutations and delivery to dystrophic (mdx) muscle

靶向校正基因转换 (TCGC)：在 DMD 突变和递送至营养不良 (mdx) 肌肉中的应用

• 批准号: nhmrc : 299946
• 负责人: A/Pr Andrew Kornberg
• 金额: $ 33.11万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2004
• 资助国家: 澳大利亚
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/targeted-corrective-gene-mdx-muscle/82997
• 关键词: Targeted; Corrective; Gene; Conversion; TCGC

The muscular dystrophies are inherited diseases that lead to muscle wastage and severe disabilities. The most severe forms result in the early death of newborns, but a large number are diagnosed in children showing early mild symptoms and progress steadily to severe disabling forms in the juvenile and young adult. Perhaps the most devastating of these dystrophies is Duchenne Muscular Dystrophy (DMD). This condition affects 1 in 3,300 boys, who show symptoms at around 5 years of age until wheelchair confinement by early teens. DMD boys undergo major clinical and surgical treatments which at present only provide small but significant improvements to their lives. The median age at death for Duchenne boys is 22 years. The cause of DMD has been known for almost 2 decades and is a defect in just a single component of muscle, Dystrophin which is produced by muscle cells. In general, boys with DMD possess Dystrophin which is missing an important part that prevents the breakdown of muscles during activity. As a consequence, all the muscles in DMD boys slowly break down over their lifetime until they die because the muscle which helps in drawing breath (Diaphragm) is no longer capable of helping them to breathe. The muscle component Dystrophin is produced by a gene (the dys gene) and the defect of Dystrophin is caused by a defect in the dys gene. If the dys gene defect was able to be corrected in boys with DMD, their Dystrophin may also be corrected and the breakdown of their muscle prevented. We have been able to correct the dys gene in muscle cells from a mouse with DMD. We wish to improve this technology and allow muscle to be corrected with genetically corrected fibres to form a basis for treatment of human DMD. In this way we hope to significantly improve and lengthen these boys' lives and even lead to a cure for DMD and other genetic muscle disease

肌肉萎缩症是遗传性疾病，导致肌肉浪费和严重残疾。最严重的形式会导致新生儿过早死亡，但大量儿童被诊断出早期表现出轻微症状，并在青少年和年轻人中逐渐发展为严重残疾形式。也许这些营养不良中最具破坏性的是杜氏肌营养不良症（DMD）。这种情况影响了3,300名男孩中的1名，他们在5岁左右出现症状，直到十几岁时坐轮椅。DMD男孩接受主要的临床和手术治疗，目前只能为他们的生活提供小但显着的改善。杜兴男孩的死亡年龄中位数为22岁。DMD的原因已经知道了近20年，并且是肌肉的一种成分缺陷，肌营养不良蛋白是由肌肉细胞产生的。一般来说，患有DMD的男孩拥有Dystrophin，它缺少一个重要的部分，可以防止肌肉在活动中分解。因此，DMD男孩的所有肌肉在他们的一生中慢慢分解，直到他们死亡，因为帮助呼吸的肌肉（横膈膜）不再能够帮助他们呼吸。肌营养不良蛋白是由一个基因（dys基因）产生的，而肌营养不良蛋白的缺陷是由dys基因的缺陷引起的。如果dys基因缺陷能够在DMD男孩中得到纠正，他们的Dystrophin也可能得到纠正，并防止他们的肌肉分解。我们已经能够纠正DMD小鼠肌肉细胞中的dys基因。我们希望改进这项技术，并允许用基因校正的纤维来校正肌肉，以形成治疗人类DMD的基础。通过这种方式，我们希望能显著改善和延长这些男孩的生命，甚至导致DMD和其他遗传性肌肉疾病的治愈